Current therapies for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are unsatisfactory, During the past year, we and three other groups discovered that U2AF1 and seven other components of the pre-mRNA splicing complex are recurrently mutated in patients with MDS and AML. Small molecule modulators of this complex have,been developed by our collaborators and others. The most advanced compounds in this class (called sudemycins) are soluble, stable, active against tumor xenografts in mice, non-toxic to normal cells, and can be synthesized in gram quantities. Sudemycins bind the SF3b splicing complex and induce apoptosis in cell lines after brief exposure, in part by causing alternative splicing of MDM2, a negative regulator of P53. The long-term goal of this proiect is to develop RNA splicing modulators as targeted therapv for MDS and AML, Our preliminary data demonstrate enhanced sensitivity of cells expressing mutant U2AF1 to sudemycin. We hypothesize that mutations in RNA splicing machinery confer sensitivity to splicing modulators by dysreguiating expression of alternatively spliced products that contribute to MDS/AML pathogenesis. We will test this hypothesis using well-defined systems in vitro and in vivo.
In Specific Aim 1, primary human AML myeloblasts with or without splicing gene mutations, based on completed sequencing of all coding genes in these samples, will be used to assess the impact of sudemycins (and other splicing modulators) on growth, viability, apoptosis, and cell cycle kinetics in vitro and chimerism, apoptosis, and trilineage differentiation in vivo after xenotransplantation into immune deficient mice. This will determine whether splicing gene mutations serve as biomarkers of sensitivity to these drugs.
In Specific Aim 2, we will discover alterations in the transcriptome induced by splicing modulators and develop sensitive and quantitative assays for assessment of the on-target effects of these agents. This project addresses SPORE translational endpoints by identifying genetic biomarkers that are predictive of response to splicing modulators and by developing assays that will be used for pharmacodynamic monitoring in clinical trials of splicing modulators:

Public Health Relevance

Current chemotherapy treatments cure a minority of patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We and others have recently discovered that RNA splicing, a critical metabolic pathway, is altered in many of these patients and compounds that modulate this pathway are available. This project will test the activity of this novel class of compounds in human cells and develop assays and preclinical data needed to initiate clinical trials of these agents in patients with MDS or AML.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA171963-05
Application #
9368251
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Kuzmin, Igor A
Project Start
Project End
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wagner, Julia A; Berrien-Elliott, Melissa M; Rosario, Maximillian et al. (2017) Cytokine-Induced Memory-Like Differentiation Enhances Unlicensed Natural Killer Cell Antileukemia and Fc?RIIIa-Triggered Responses. Biol Blood Marrow Transplant 23:398-404
Uy, G L; Duncavage, E J; Chang, G S et al. (2017) Dynamic changes in the clonal structure of MDS and AML in response to epigenetic therapy. Leukemia 31:872-881
Saez, Borja; Walter, Matthew J; Graubert, Timothy A (2017) Splicing factor gene mutations in hematologic malignancies. Blood 129:1260-1269
Cooper, Matthew L; Choi, Jaebok; Karpova, Darja et al. (2017) Azacitidine Mitigates Graft-versus-Host Disease via Differential Effects on the Proliferation of T Effectors and Natural Regulatory T Cells In Vivo. J Immunol 198:3746-3754
Duncavage, Eric J; Uy, Geoffrey L; Petti, Allegra A et al. (2017) Mutational landscape and response are conserved in peripheral blood of AML and MDS patients during decitabine therapy. Blood 129:1397-1401
Shirai, Cara Lunn; White, Brian S; Tripathi, Manorama et al. (2017) Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome. Nat Commun 8:14060
Schroeder, Mark A; Choi, Jaebok; Staser, Karl et al. (2017) The Role of Janus Kinase Signaling in Graft-Versus-Host Disease and Graft Versus Leukemia. Biol Blood Marrow Transplant :
How, Joan; Slade, Michael; Vu, Khoan et al. (2017) T Cell-Replete Peripheral Blood Haploidentical Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide Results in Outcomes Similar to Transplantation from Traditionally Matched Donors in Active Disease Acute Myeloid Leukemia. Biol Blood Marrow Transplant 23:648-653
Ali, Alaa M; Weisel, Daniel; Gao, Feng et al. (2017) Patterns of infectious complications in acute myeloid leukemia and myelodysplastic syndromes patients treated with 10-day decitabine regimen. Cancer Med 6:2814-2821
Romee, Rizwan; Rosario, Maximillian; Berrien-Elliott, Melissa M et al. (2016) Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci Transl Med 8:357ra123

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